PROJECT SUMMARY Energy supply to the ear is critical for hearing function since the ear is one of the highest energy consuming organs. Insufficient energy can result from insufficient blood flow to the cochlea contributing to a wide range of clinical hearing disorders such as loud sound-induced hearing loss, hearing loss related to ageing, and sudden deafness, which can largely impact the quality of human life by causing individual communication problems and social isolation. We believe that success in repair and regeneration of hearing function following loss of sensory cells requires parallel restoration or maintenance of an efficient blood supply. The proposed research is part of a longer range study on the role of pericytes in the physiology of the cochlea, but is specifically focused on the pericyte pathology that occurs in loud sound-induced lateral wall microcirculatory dysfunction. Pericytes are multipotent mesenchymal-like cells and are primarily located on microvessels. Normal function of pericytes is vital for blood flow regulation, vascular integrity, angiogenesis and tissue fibrogenesis. Pericyte pathology is profoundly associated with many organ diseases such as brain stroke, heart infarction, and retinal failure. Therapeutic targeting of pericytes has been considered a novel treatment for many of those clinical diseases. Cochlear pericytes are extremely vulnerable and sensitive to damage, but are critical for regulation of cochlear blood flow and maintaining tightness of the blood-labyrinth barrier in the stria vascularis. More specifically they are highly responsive to stress such as acoustic trauma. Upon exposure to loud sound, cochlear pericytes undergo striking changes in their biological properties, but the molecular mechanisms that underline those changes have not yet been studied. In this five year proposal, we will determine what molecular signals lead to loud sound-induced pericyte migration away from the capillaries and their phenotype changes. We will also determine whether transplantation of fresh pericytes such as neo-pericytes (derived from neonatal mice) to noise-damaged cochlea can repair loud sound-damaged microvessels and restore vascular function. The success of each aim will inevitably lead to the development of new protective and restorative therapies for a normal blood flow to cochlea? the critical foundation of hearing preservation or/and restoration.